KR20070041537A - Topical antiviral formulations - Google Patents

Abstract

The present invention provides nucleotide reverse transcriptase inhibitors (NRTIs) suitable for topical application, preferably [2- (6-Amano-purin-9-yl) -1-methyl-ethoxymethyl] -phosphonic acid (tenofovir, PMPA ) Or physiologically functional derivatives thereof and their use in the prevention of HIV infection.

HIV infection prevention, NRTI, topical application, tenofovir, PMPA

Description

Topical antiviral agents {TOPICAL ANTIVIRAL FORMULATIONS}

The present invention relates to compound preparations having antiviral activity, more specifically to compound preparations having anti-HIV properties.

Human immunodeficiency virus (HIV) infections and related diseases are important public health issues worldwide. One approach to the HIV / AIDs problem is to reduce the risk of new infections by reducing the risk of transmission of HIV. Even if treatment or treatment is available, infection prevention in the early stages will remain the first line of defense. For medical, psychological and economic reasons, prevention of early AIDS infection is preferred over treatment.

Training on STDs and their transmission methods and the so-called "safe sex" technology has been considered a guarantee to reduce the risk of STD transmission through sexual activity. Review of blood supply has helped to reduce the risk of transmission of STD-induced bacteria through transfusion and related medical practice. Despite the known prevention of STD, current safe sex techniques are not always used or not always used for many reasons (for example, carelessness, ignorance, inappropriate skills, cultural barriers, unplanned or impulsive sex, etc.). . Moreover, even if used, safe sex techniques (except abstinence) are not always effective.

Various vaginal creams and ointments are currently available. Nonoxynol-9, orthoxynol-9 and benzalkonium chloride are generally available as suppositories, inserts, creams, films, foams, gels. Examples of such products include KY Plus ^™ . (2.2% nonoxynol-9; Advanced Care Products, Raritall, NJ); Encare ^™ . (3% nonoxynol-9; Thompson Medical Co., West Palm Beach, Fla.); Gynol II (Advanced Care Products, Raritan, NJ); Ortho Options Conceptrol (Advanced Care Products, Raritan, NJ); Semicid (Whitehall Robbins Healthcare, Madison, NJ); and Advantage-S (Columbia Laboratories, Aventura, Fla.) Include.

However, no formulation is completely effective against HIV. It would therefore be desirable to provide improved compositions and methods that reduce the risk of HIV transmission and / or infection during sexual activity.

[Summary of invention]

The present invention is directed to nucleotide reverse transcriptase inhibitors (NRTIs) suitable for topical (eg vaginal, rectal, etc.) applications, preferably [2- (6-amano-purin-9-yl) -1-methyl- Methoxymethyl] -phosphonic acid (tenofovir, PMPA) or physiologically functional derivatives thereof, and their use in the prevention of HIV infection.

The present invention generally relates to compositions and methods for preventing and / or reducing the risk of HIV transmission through sexual activity. Although primarily associated with intersex sex (ie, vaginal intercourse between male / female), the compositions of the present invention can also be used by a group of other types of sexual activity. For example, the compositions of the present invention can be used by populations having anal sex (male / female liver or male / male liver); When the composition of the present invention is used for anal intercourse, it is preferable to adjust the buffering capacity of the composition to correspond to the pH value usually found in the rectum and to control the lubricity of the formulation.

In heterosexual intercourse through the vagina, the composition may be inserted into the vagina before intercourse. For anal intercourse (hetero or homo liver), the composition can be inserted into the rectum prior to intercourse. In either vaginal or anal intercourse, the composition can also act as a lubricant. For further prevention, it is desirable to use condoms, if appropriate, before sexual intercourse or other sexual activity. For better prevention, the composition can be reused as soon as possible after the sexual activity is completed.

Spices, fragrances, fragrances and pigments may also be added to the composition as long as they do not interfere with the safety and efficacy of the composition. Indeed, the addition of spices, fragrances, fragrances and pigments to the compositions of the present invention will increase the likelihood that the compositions will be used during sexual activity.

The method of the present invention has the advantage that it can be used for the prevention of various kinds of sexual activity (vaginal or anal) by heterosexual, bisexual and homosexual. Another advantage of the method of the present invention for reducing HIV transmission is that it is easiest to implement and / or use the method in the context of insertion. Thus, a woman may use the method to protect her (even her and her counterpart), either with or without her partner's knowledge of the use of the method. In addition, the partner will not have to rely on the male or female partner's demand for non-AIDS or consent to condom use for prevention. One or both sex groups (particularly women) can start and implement the use of this method. This method is preferably used before sexual activity, most preferably both before and after sexual activity. In addition, there is an additional advantage that the compositions of the present invention are also useful for the prevention and / or treatment of bacterial vaginosis.

The present invention is described in detail with reference to specific embodiments, examples of which are illustrated in the accompanying drawings. While the invention will be described in conjunction with the listed embodiments, the invention is not limited to such embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents falling within the scope of the invention as defined by the claims.

Justice

Unless otherwise stated, terms and expressions used in the present invention shall have the following meanings.

The term "physiologically functional derivative" means a pharmaceutically active compound having a physiological function that is equivalent to or nearly equivalent to a given NRTI. In the present invention, the term "physiologically functional derivative" includes: physiologically acceptable salts, ethers, esters, prodrugs, solvates, enantiomers, diastereomers or stereoisomerically enriched racemic mixtures. And stereoisomers and any compound that can provide (directly or indirectly) such compounds or antivirally active metabolites or residues thereof when administered to a subject.

"Bioavailability" refers to the extent to which a pharmaceutical active is made available to target tissues after administration in the body. Increasing the bioavailability of the pharmaceutically active agent can provide a more efficient and effective treatment to the patient at a given dose, since more pharmaceutically active agent is available in the tissue of interest.

Combination compounds of the present invention may be referred to as "active ingredients" or "pharmaceutically active agents".

As used herein, the term “prodrug” refers to a drug, ie, active ingredient, that results from spontaneous chemical reaction (s), enzyme catalyzed chemical reaction (s), and / or metabolic chemical reaction (s) when administered to a biological system. Refers to all compounds made.

"Prodrug portion," is in the in the cell, metabolism, mean a hydrolysis, enzymatic degradation or labile functional group that is separated from the active inhibitory compound by a different particular process (Bundgaard, Hans, "Design and Application of Prodrugs" in Textbook of Drug Design and Developnent (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Prodrug moieties can be used to enhance solubility, absorption and lipophilic properties to volume drug delivery, bioavailability and effects. Thus, “prodrugs” are covalently modified analogs of a therapeutically active compound.

"Alkyl" means a saturated or unsaturated branched, straight chain, cyclic hydrocarbon radical derived by removing one hydrogen atom from one carbon atom of a parent alkan, alkene or alkyne. Typical alkyl groups consist of 1 to 18 saturated and / or unsaturated carbons, such as ordinary, secondary, tertiary or cyclic carbon atoms. Non-limiting examples of alkyl groups include the following: methyl, Me (-CH ₃ ), ethyl, Et (-CH ₂ CH ₃ ), acetylenic (-C≡CH), ethylene, vinyl (-CH = CH ₂ ) 1-propyl, n- Pr, n -propyl (-CH ₂ CH ₂ CH ₃ ), 2-propyl, i -Pr, i -propyl (-CH (CH ₃ ) ₂ ), aryl (-CH ₂ CH = CH ₂ ), propargyl (-CH ₂ C≡CH), cyclopropyl (-C ₃ H ₅ ), 1-butyl, n- Bu, n -butyl (-CH ₂ CH ₂ CH ₂ CH ₃ ) , 2-methyl-1-propyl, i- Bu, i -butyl (-CH ₂ CH (CH ₃ ) ₂ ), 2-butyl, s -Bu, s -butyl (-CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl, t- Bu, t -butyl (-C (CH ₃ ) ₃ ), 1-pentyl, n -pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2- Pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), Cyclopentyl (-C ₅ H ₉ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH = CH ₂ ), 1-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), cyclohexyl (-C ₆ H ₁₁ ), 2 -Methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl -2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ ) (CH ₂ CH ₃ ) ₂ ), 2-methyl-3- Pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ) and 3,3-dimethyl-2 -Butyl (-CH (CH ₃ ) C (CH ₃ ) _{3 )} .

"Aryl" means a monovalent aromatic hydrocarbon radical having 6 to 20 carbon atoms derived by removing one hydrogen atom from one carbon atom of the parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.

"Arylalkyl" is a carbon atom, typically terminal or SP ³ One of the hydrogen atoms bonded to a carbon atom is replaced by an aryl radical Refers to acyclic alkyl radicals. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthyl Ten-l-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. For example, the arylalkyl group having 6 to 20 carbon atoms has 1 to 6 carbon atoms, and the aryl portion has 5 to 14 carbon atoms, including the alkanyl, alkenyl or alkynyl group.

"Substituted alkyl", "substituted aryl", "substituted arylalkyl" refers to alkyl, aryl, arylalkyl, wherein one or more hydrogen atoms are independently replaced with a substituent. Typical substituents include, but are not limited to, -X, -R, -O, -OR, -SR, -S, -NR ₂ , -NR ₃ , = NR, -CX ₃ , -CN, -OCN,- SCN, -N = C = O, -NCS, -NO, -NO ₂ , = N ₂ , -N ₃ , NC (= O) R, -C (= O) R, -C (= O) NRR- S (= O) ₂ O-, -S (= O) ₂ OH, -S (= O) ₂ R, -OS (= O) ₂ OR, -S (= O) ₂ NR, -S (= O ) R, -OP (= O) O ₂ RR, -P (= O) O ₂ RR, -P (= O) (O) ₂ , -P (= O) (OH) ₂ , -C (= O R, -C (= O) X, -C (S) R, -C (O) OR, -C (O) O, -C (S) OR, -C (O) SR, -C (S ) SR, -C (O) NRR, -C (S) NRR, -C (NR) NRR, wherein each X is independently halogen: F, Cl, Br, or I; Each R is independently —H, alkyl, aryl, heterocycle or prodrug moiety.

"Heteroaryl" and "heterocycle" refer to ring systems in which one or more ring atoms are heteroatoms (eg, nitrogen, oxygen, sulfur (as opposed to carbon)). Heterocycles are described as follows: Katritzky, Alan R., Rees, CW, and Scriven, E. Comprehensive Heterocyclic Chemistry (1996) Pergamon Press; Paquette, Leo A .; Principles of Modern Heterocyclic Chemistry WA Benjamin, New York, (1968), especially Chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), especially 13, 14, 16, 19 and 28. Representative heterocycles include, but are not limited to, pyrrole, Indole, furan, benzofuran, thiophene, benzothiophene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinoryl, 3-quinoryl, 4-quinoryl, 2-imidazole, 4 -Imidazole, 3-pyrazole, 4-pyrazole, pyridazine, pyrimidine, pyrazine, purine, cynoline, phthalazine, quinazoline, quinoxaline, 3- (l, 2,4-N) -tria Zolyl, 5- (l, 2,4-N) -triazolyl, 5-tetrazolyl, 4- (l-0,3-N) -oxazole, 5- (l-0,3-N) -oxa Sol, 4- (lS, 3-N) -thiazole, 5- (1-S, 3-N) -thiazole, 2-benzoxazole, 2-benzothiazole, 4- (1,2,3- N) -benzotriazole and benzimidazole.

Stereochemical definitions and definitions used in the present invention are described in SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in forms with optical activity. That is, they can rotate the plane of plane polarization. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute arrangement of molecules with respect to the hand symmetry center. The prefixes d and l or (+) and (-) indicate the rotational representation of planar polarization by the compound, where (-) or l means that the compound is left-bounded. Compounds with the prefix (+) or d have priority. In a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of each other. Special stereoisomers may also be called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. The 50:50 mixture of enantiomers is called a racemic mixture or racemate. The terms "racemic mixture" and "racemate" refer to mixing of two enantiomers in the same molar number, thus having no optical activity.

The term "chiral" refers to a molecule whose properties are such that the mirror pairs cannot overlap each other, and the term "achiral" refers to a molecule that can overlap with the mirror pair.

The term “stereoisomers” has the same chemical structure, but the arrangement of atoms or groups in space refers to different compounds.

"Diastereoisomers" refer to stereoisomers that have two or more hand symmetric centers so that the molecules are mirror images of one another. Diastereomers differ in physical properties, for example in melting point, breaking point, spectral properties and reactivity. Mixtures of diastereomers can be separated through higher resolution analytical processes such as electrophoresis and chromatography.

"Enantiomers" refer to two stereoisomeric compounds that cannot be enclosed completely with one another in a mirror image.

"Nucleoside and nucleotide reverse transcriptase inhibitors" or "NRTIs" include compounds that exhibit anti-HIV effects by inhibiting HIV reverse transcriptase activity. Examples include, but are not limited to, abacavir (ABC), didanosine (ddl), emtricitabine (FTC), lamivudine (3TC), stavudine (d4T)), tenofovir (TFV), zidovudine (AZT) and zalcitabine (ddC) and their physiologically functional derivatives. One or more NRTIs can be used in the formulations of the present invention.

"Topical" formulations include those suitable for administration through the nose, oral cavity, rectum, skin and vagina.

PMPA or tenofovir (US Pat. Nos. 4,808,716, 5,733,788, 6,057,305) have the following structure:

The chemical names of PMPA, tenofovir, include: (R) -9- (2-phosphonylmethoxypropyl) adenine; And phosphonic acid, [[(lR) -2- (6-amino-9H-purin-9-yl) -l-methylethoxy] methyl]. The CAS registration number is 147127-20-6. Tenofovir disoproxil fumarate (DF) is a nucleotide reverse transcriptase inhibitor approved in the United States for use in combination with other antiretroviral agents in the treatment of HIV-1 infection. Tenofovir disoproxil fumarate i.e. Viread ^® (Gilead Science, Inc.) is the fumarate salt of tenofovir disoproxil. Viread ^® may be named as follows: 2,4,6,8- tetrahydro-5-oxa force Fano Nadi acid, 5 - [[(1R) -2- (6- Amino-purin-9--9H- Yl) -l-methylethoxy] methyl]-, bis (l-methylethyl) ester, 5-oxide, (2E) -2-butenedioate (1: 1). The CAS registration number is 202138-50-9.

Physiologically functional derivatives of tenofovir include PMEA and PMPA compounds. PMEA and PMPA have the following structure:

Wherein R ³ is H for PMEA and R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl or CH ₂ OR ⁸ (R ⁸ is C ₁ -C ₆ alkyl, C _{1 for} PMPA) -C ₆ hydroxyalkyl or C ₁ -C ₆ haloalkyl). R ⁶ and R ⁷ are independently H or C ₁ -C ₆ alkyl. R ⁴ and R ⁵ are independently H, NH ₂ , NHR or NR ₂ , where R is C ₁ -C ₆ alkyl. R ¹ and R ² are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₆ -C ₂₀ arylalkyl, C ₆ -C ₂₀ substituted arylalkyl, acyloxymethyl ester -CH ₂ OC (= 0) R ⁹ (e.g. POM) or acyloxymethyl carbonate -CH ₂ OC (= 0) OR ⁹ (e.g. POC) R ⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl). For example, R ¹ and R ² are pivaloyloxymethoxy, POM, -CH ₂ OC (= 0) C (CH ₃ ) ₃ or POC, -CH ₂ OC (= 0) OC (CH ₃ ) ₃ Can be. In addition, for example, tenofovir R ³ is CH ₃ , and R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ And R ⁷ has a structure of H. Dialkyl phosphonates can be prepared by the following methods: Quast et al. (1974) Synthesis 490; Stowell et al. (1990) Tetrahedron Lett. 3261; US Patent No. 5,663,159.

PMPA can be enriched enantiomers or pure (single stereoisomers), ie the carbon atoms comprising R ³ are R or S enantiomers. PMPA may be a racemate, ie a mixture of R and S stereoisomers.

The present invention includes all enantiomers, diastereomers, racemates, enhanced stereoisomeric mixtures of PMPA and physiologically functional derivatives thereof.

The present invention includes all prodrugs of tenofovir. A number of structurally diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress). in Medicinal Chemistry 34: 112-147 (1997). A commonly used class of prodrugs is acyloxyalkyl esters, which are first used as prodrug methods for carboxylic acids and then for phosphates and phosphonates (Farquhar et al. (1983) J. Pharm . Sci . 72: 324) . And US Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756). Acyloxyalkyl esters were then used to increase the delivery and oral bioavailability of phosphonic acid through the cell membrane. Alkoxycarbonyloxyalkyl esters, a similar variation of the acyloxyalkyl ester process, can increase oral bioavailability as prodrug portion of the combined compounds of the present invention. It has been reported that aryl esters of the phosphorus group, especially phenyl esters, can enhance oral bioavailability (DeLambert et al. (1994) J. Med . Chem. 37: 498). Phenyl esters with carboxyl esters in the ortho position for phosphates have also been described (Khamnei and Torrence, (1996) J. Med . Chem . 39: 4109-4115). Benzyl esters have been reported to produce parent phosphonic acid. In some cases, substituents in the ortho- or para-position may accelerate the hydrolysis. Benzyl analogs with acylated or alkylated phenols can produce phenolic compounds through enzymatic actions such as, for example, ester hydrolases and oxidases, which cleave the CO bonds of benzyl to phosphoric acid and quinone metides. To form an intermediate. Examples of prodrugs of this kind are described in Mitchell et al . (1992) J. Chem . Soc . Perldn Trans . 1 2 3 4 5; Brook et al., Described in WO 91/19721. As another benzyl prodrug, the attachment of carboxyl esters to benzyl methylene has been described (Glazier et al., WO 91/19721). Thio containing prodrugs have been reported to be useful for intracellular delivery of phosphonate drugs. Such prodrug esters include ethylthio groups in which thiol groups are esterified by acyl groups or combine with other thiol groups to form disulfides. This deesterification or reduction of disulfides results in free thio intermediates, which in turn are separated into phosphoric acid and episulfide (Puech et al. (1993) Antiviral ). Res . , 22: 155-174; Benzaria et al. (1996) J. Med . Chem . 39: 4958). Cyclic phosphonate esters are also described as phosphorus containing prodrug compounds.

Prodrug esters according to the invention are independently selected from the following groups: (1) mono-, di-, and tri-phosphate esters of tenofovir or administered to the human body (directly or indirectly) such mono-, di- -And compounds capable of providing tri-phosphate esters; (2) carboxylic acid esters (3) sulfonate esters such as alkyl- or aralkylsulfonyl (eg methanesulfonyl); (4) amino acid esters (eg, alanine, L-valyl or L-isoleucine); (5) phosphonates; And (6) phosphonamidate esters. The ester groups (l)-(6) may be substituted with the followings; C ₁ -C ₁₈ straight or branched alkyl (eg methyl, n-propyl, i-butyl or n-butyl); C ₃ -C ₁₂ cycloalkyl; Alkoxyalkyl (eg methoxymethyl); Arylalkyl (eg benzyl); Aryloxyalkyl (eg phenoxymethyl); C ₅ -C ₂₀ aryl (eg, phenyl optionally substituted with halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy); Or amino. Representative aryl moieties present in such esters include phenyl or substituted phenyl groups. US Patent No. 6312662; Jones et al. (1995) Antiviral Research 27: 1-17; Kucera et al. (1990) AIDS Res . Hum . Retro Viruses 6: 491-501; Piantadosi et al. (1991) J. Med . Chem . 34: 1408-14; Hosteller et al. (1992) Antimicrob . Agents Chemother . 36: 2025-29; Hostetler et al. (1990) J. Biol . Chem . 265: 611127; And Siddiqui et al. (1999) J. Med . Chem . 42: 4122-28 describe many phosphate prodrug moieties.

Pharmaceutically acceptable prodrugs refer to compounds which are metabolized in the host by enzymatic action or general acid or base solvation degradation, such as for example hydrolysis or oxidation, to form the active ingredient. Typical examples of active ingredient prodrugs of the combinations of the present invention have a biolabile protecting group in the functional group portion of the active compound. Prodrugs may be oxidized, reduced, aminated, deaminated, esterified, deesterified, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated or form chemical bonds to the prodrugs And compounds that can change or convert to other functional groups, including disrupting.

The description of the foregoing compounds may also apply mutatis mutandis to their physiologically acceptable salts. Examples of physiologically acceptable salts and physiologically acceptable derivatives of tenofovir include alkali metals (eg sodium), alkaline earth metals (eg magnesium), ammonium and NX ₄ ⁺ , where X is C ₁ −. Salts derived from an appropriate base, such as C ₄ alkyl). Physiologically acceptable salts of hydrogen atoms or amino groups include salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, succinic acid; Organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; And inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid. Physiologically acceptable salts of hydroxyl compounds include anions of such compounds in combination with appropriate cations such as Na ⁺ and NX ₄ ⁺ , where X is independently selected from H or C ₁ -C ₄ alkyl groups.

For therapeutic use, the salts of the active ingredients of the invention must be physiologically usable, ie, salts derived from physiologically acceptable acids or bases. However, physiologically acceptable acids or bases may also be used, for example in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, fall within the scope of the present invention.

Formulations include those suitable for nasal, mouth, rectal, skin and vaginal administration.

Formulations suitable for oral topical administration usually include lozenges comprising the active ingredient in an aromatic base such as sucrose, acacia or tragacanth gum; Pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; Mouthwashes comprising the active ingredient in a suitable liquid carrier are included. Formulations for rectal administration are presented in the form of suppositories with suitable bases including, for example, cocoa butter. Formulations suitable for vaginal administration are presented as tablets, suppositories, tampons, creams, gels, pastes, foams or spray formulations containing the active ingredient, together with vehicles known to be suitable in the art.

As the carrier is a solid, the pharmaceutical preparation suitable for rectal administration is most preferably a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Typically suppositories are prepared by mixing the active ingredient with a softened or melted carrier, followed by cooling and molding in a mold.

In the context of the present invention, it is to be understood that the term topical application includes not only the skin but also the application in the body cavity. Thus, in a preferred embodiment, NRTI is applied to a body cavity such as the anus, oral cavity or vagina. In a particularly preferred embodiment, NRTI is applied to the quality. The method of the present invention thus comprises topical application to the vagina for the prevention of HIV infection through vaginal intercourse. Generally, topical application takes place from 0 to 60 minutes, preferably 0 to 5 minutes, before the onset of vaginal intercourse.

NRTI can be applied to the vagina in various forms, such as sprays, foams, jellies, creams, suppositories, pills, and tampo. Compositions suitable for vaginal application are described in U.S. Pat. , 4,371,518, 4,389,330, 4,415,585 and 4,551,148, and the method of the present invention can be performed by applying NRTI to the vagina in the form of such a composition. Compositions comprising NRTIs can be applied to the vagina in any existing manner. Suitable devices for applying the composition to the vagina are disclosed in US Pat. Nos. 3,826,828, 4,108,309, 4,360,013 and 4,589,880, which are incorporated herein by reference.

In another embodiment, the present invention comprises topical administration of an NRTI to the anus. Compositions to be administered to the anus are suitably foams, creams, jelly and the like, as described above for vaginal application. When applied to the anus, it is desirable to use an applicator that allows the composition to be applied evenly through the anus. For example, a suitable applicator is a tube of 2.5 cm to 25 cm, preferably a tube of 5 cm to 10 cm, with a hole allowing constant application along the length.

In another embodiment, the method may apply the NRTI to the oral cavity. For oral application, it is appropriate to use the composition in the form of a mouthwash or gargle. Oral application is particularly preferred in the prevention of infection during dental procedures. The composition is preferably applied regularly immediately before and during the course of the dental course.

The present invention also provides a composition useful for preventing the spread of HIV infection. As mentioned above, such compositions may be in the form of foams, creams, jellies, suppositories, pills, nebulizers, gargles, mouthwashes and the like, particularly preferred are gels for vaginal use. The concentration of NRTI in the composition should be such that it will have an effect on the local anus, oral cavity or vagina by the usual dosage of the type of composition applied. In this regard, when the composition is in the form of suppositories (including vaginal suppositories), suppositories are typically 1 to 5 grams, preferably about 3 grams, and all suppositories are used. For vaginal tablets, 1 to 5 grams, preferably about 2 grams, are suitable and all tablets are used. If the composition is a vaginal cream, 0.1 to 2 grams, preferably about 0.5 grams of cream are used. If the composition is a water soluble vaginal cream, 0.1 to 2 grams, preferably about 0.6 grams, are used. If the composition is a vaginal spray foam, 0.1 to 2 grams, preferably about 0.5 grams, are used. If the composition is an anal cream, 0.1 to 2 grams, preferably about 0.5 grams, are used. If the composition is an anal spray foam, 0.1 to 2 grams, preferably about 0.5 grams, are used. If the composition is a mouthwash or gargle, 1 to 10 ml, preferably about 5 ml is used.

In the case of mouthwashes or gargles, it is preferred to include an agent in the composition that can mask the taste and / or odor of the NRTI. Such agents include flavoring agents used in typical mouthwashes and gargles, such as peppermint, cinnamon, and the like.

The compositions of the present invention may also be in the form of sustained release compositions. In this embodiment, an NRTI is released in the composition which releases the active ingredient at a rate that results in an effective NRTI's vaginal or anal concentration. Sustained release compositions are described in Controlled Release of Pesticides and Pharmaceuticals, D. H. Lew, Ed., Plenum Press, New York, 1981; And U.S. Patent number 5,185,155; 5,248,700; 4,011,312; 3,887,699; 5,143,731; 3,640,741; 4,895,724; 4,795,642; Bodmeier et al., Journal of Pharmaceutical Sciences, vol. 78 (1989); Amies, Journal of Pathology and Bacteriology, vol. 77 (1959); And Pfister et al., Journal of Controlled Release, vol. 3, pp. 229-233 (1986), all of which are incorporated herein by reference.

The composition of the present invention may be in the form of releasing an NRTI by work such as vaginal or anal intercourse. For example, the composition may comprise NRTIs in vesicles or liposomes, which rupture by mechanical action during intercourse. Compositions comprising liposomes are described in U.S. Pat. Patent No. 5,231, 112 and Deamer and Uster, "Liposome Preparation: Methods and Mechanisms", in Liposomes, pp. 27-51 (1983); Sessa et al., J. Biol. Chem., Vol. 245, pp. 3295-3300 (1970); Journal of Pharmaceutics and Pharmacology, vol. 34, pp. 473-474 (1982); And Topics in Pharmaceutical Sciences, D. D. Breimer and P. Speiser, Edsv Elsevier, New York, pp. 345-358 (1985), incorporated herein by reference.

It should be noted that the compositions of the present invention also relate to articles such as intrauterine contraceptive devices (IUD), diaphragms, vaginal sponges, vaginal condoms, and the like. For IUDs or vaginal diaphragms, sustained and / or mechanical-release compositions are preferred, whereas for condoms, mechanically release compositions are preferred.

In another embodiment, the present invention provides new articles useful for the prevention of HIV infection. In particular, the article of the present invention is to release the NRTI when placed in the appropriate body part or body cavity. Accordingly, the present invention provides IUDs, diaphragms, vaginal sponges, vaginal preparations or condoms containing or associated with an NRTI.

Thus, the article of the present invention may be an IUD comprising one or more NRTIs. Suitable IUDs are disclosed in US Pat. Nos. 3,888,975 and 4,283,325, which are incorporated by reference herein. The article of the present invention may be an intravaginal sponge which contains the NRTI in a time controlled manner. Intravaginal sponges are disclosed in US Pat. Nos. 3,916,898 and 4,360,013, which are incorporated by reference herein. The article of the invention may also be a vaginal dispenser that releases an NRTI. Vaginal dispensers are disclosed in US Pat. No. 4,961,931, which is incorporated herein by reference.

The article of the invention can also be a condom coated with NRTI. In a preferred embodiment, the condom is coated with a lubricant or penetration enhancer comprising NRTI. Lubricants and penetration enhancers are described in US Pat. No. 4,537,776; 4,552,872; 4,557,934; 4,130,667, 3,989,816; 4,017,641; 4,954,487; 5,208,031; And 4,499,154, which are incorporated herein by reference.

The following examples detail and demonstrate embodiments within the scope of the invention. The following examples are for illustrative purposes only, and various modifications may be made without departing from the spirit and scope of the invention, and therefore the scope of the invention should not be construed as limited to these embodiments. The following experimental examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way. "Active ingredient" refers to one or more NRTIs, preferably tenofovir or physiologically functional derivatives thereof, as defined above.

Formulation A (controlled release formulation):

This formulation is prepared by wet granulation of various components with purified water, followed by compression by adding magnesium stearate. Hypromellose can be used for viscosity grade changes.

mg /tablet

Active ingredient 300

Hypromellose 112

Lactose Monohydrate 53

Pregelatinized Starch 28

Magnesium Stearate 7

Sufficient amount of purified water

Drug release occurs over about 6-8 hours, ending after 12 hours.

Formulation B (controlled release capsule):

The following controlled release capsule formulations are prepared by wet granulating the components a, b, c and e, extruding using an extruder, and then extruding the extrudate and drying. The dried pellets are coated with a release control film (d) or polymer. The final product is filled into two pieces, hard gelatin or hydroxypropyl methylcellulose capsules.

mg /capsule

(a) active ingredient 300

(b) microcrystalline cellulose 125

(c) lactose monohydrate 125

(d) ethyl cellulose 13

(e) sufficient amount of purified water

(f) gelatin capsules

Formulation C (oral suspension):

The active ingredients are mixed with the other ingredients and filled to dry powder form. Add purified water and mix well before use.

300 mg active ingredient

Refined Sugar 2000 mg

Simethicone 300 mg

Methylparaben 30 mg

Propylparaben 10 mg

Peach flavor 500 mg

5.00 ml of purified water enough

Formulation D (Suppositories):

One fifth of Witepsol H15 is dissolved in a steam jacketed pan at up to 45 ° C. The active ingredient is filtered through 200 microsieves and mixed thoroughly until well mixed using a Silverson equipped with a cutting head in a molten base. Maintain the mixture at 45 ° C. and add the remaining Witepsol H15 to the suspension and stir to a homogeneous mixture. Stir all suspension on a 250 micron stainless steel screen and cool to 40 ° C. At 38 ° C. to 40 ° C., 2.02 g of the mixture is charged into 2 ml of a suitable plastic mold. The suppository is cooled to room temperature.

mg /suppository

Active ingredient 300

Hard Fat, B.P. (Witepsol H15-Dynamit Nobel) 1770

Formulation E (vaginal suppository)

300 mg active ingredient

Hexantriol 100 mg

Polyethylene Glycol 1500 Fill

Formulation F (vaginal cream)

300 mg active ingredient

4 g of nonionic self-emulsifying base

100 g of water

Formulation G (vaginal spray foam)

300 mg active ingredient

Polyethylene glycol 6000 2 g

2 g of nonionic emulsifier

85 g of water

10 g of Freon 12/144 (70:30)

Formulation H (vaginal gel)

Tenofovir 1.00 (% w / w)

Hydroxyethylcellulose, NF (Natrasol®250H) 2.50

Propylparaben, NF 0.02

Methylparaben, NF 0.18

Edetate Disodium, USP 0.05

Glycerin, USP 20.00

Citric Acid, USP 1.00

Purified Water, USP 75.25

Total 100.00

The pH is adjusted to 4.4 using a 10% w / w solution of sodium hydroxide and hydrochloric acid. Dissolve methylparaben and propylparaben in heated glycerin. Hydroxyethylcellulose is added and spread out to form an organic phase. After dissolving edetate disodium and citric acid in purified water, tenofovir is added to disperse, adjusted to PH 4.4, and passed through a 0.22 μm filter to clear. The aqueous phase and the organic phase are mixed, stirred well and filled with a tube or applicator.

Safety and Tolerability

Tenofovir vaginal gels with 1% BID are well tolerated in ascetic and sexually active women of HIV (-) and HIV (+) and may have beneficial effects on limited systemic absorption and vaginal microflora. Appeared to be.

The contents of each of all publications and patent applications cited herein are incorporated herein by reference.

Although the invention has been described above by way of specific embodiments, those skilled in the art will clearly appreciate that many modifications are possible without departing from the scope of the embodiments. All such modifications are also included within the scope of the claims of the present invention.

Claims (12)

A method for preventing the symptoms or effects of an HIV infection in an infected animal, the method comprising administering to said animal a prophylactically effective amount of a topical formulation containing an effective amount of NRTI in combination with a pharmaceutically acceptable carrier. The NRTI of claim 1, wherein the NRTI is [2- (6-amino-purin-9-yl) -l-methyl-ethoxymethyl] -phosphonic acid diisopropoxycarbonyloxymethyl ester (tenofovir) or A method comprising a physiologically functional derivative. The method of claim 2, wherein the formulation comprises about 0.2 to about 2 weight percent of tenofovir. The method of claim 1, wherein the NRTI comprises a physiologically functional derivative of tenofovir having the structure:

Wherein R ¹ and R ² are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₆ -C ₂₀ arylalkyl , C ₆ -C ₂₀ substituted arylalkyl, acyloxymethyl ester -CH ₂ OC (= O) R And acyloxymethyl carbonate —CH ₂ OC (═O) OR ⁹ , wherein R ⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl Is selected from; R ³ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl or CH ₂ OR ⁸ , where R ⁸ is C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl or C ₁ -C ₆ Haloalkyl); R ⁴ and R ⁵ are independently selected from H, NH ₂ , NHR and NR ₂ , where R is C ₁ -C ₆ alkyl; R ⁶ and R ⁷ are independently selected from H and C ₁ -C ₆ alkyl. Pharmaceutical formulations comprising NRTIs and pharmaceutically acceptable mediators suitable for topical application. [2- (6-Amino-purin-9-yl) -l-methyl-ethoxymethyl] -phosphonic acid diisopropoxycarbonyloxymethyl ester (tenofovir) or a pharmaceutical functional derivative thereof and for topical application Pharmaceutical formulations comprising suitable pharmaceutically acceptable mediators. The formulation of claim 5, wherein the NRTI comprises a pharmaceutical functional derivative of tenofovir having the structure

Wherein R ¹ and R ² are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₆ -C ₂₀ arylalkyl , C ₆ -C ₂₀ substituted arylalkyl, acyloxymethyl ester -CH ₂ OC (= O) R And acyloxymethyl carbonate —CH ₂ OC (═O) OR ⁹ , wherein R ⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl Is selected from; R ³ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl or CH ₂ OR ⁸ (R ⁸ is C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl or C ₁ -C ₆ halo Alkyl); R ⁴ and R ⁵ are independently selected from H, NH ₂ , NHR and NR ₂ , where R is C ₁ -C ₆ alkyl; R ⁶ and R ⁷ are independently selected from H and C ₁ -C ₆ alkyl. The gel formulation of claims 5-7. The cream formulation of claim 5. The foam formulation of claim 5. The suppository formulation of claim 5. A condom coated with the formulation of claim 5.